EP1033366A2 - Amid-Derivate mit Neuropeptid Y (NPY) -antagonistischer Wirkung - Google Patents
Amid-Derivate mit Neuropeptid Y (NPY) -antagonistischer Wirkung Download PDFInfo
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- EP1033366A2 EP1033366A2 EP00300582A EP00300582A EP1033366A2 EP 1033366 A2 EP1033366 A2 EP 1033366A2 EP 00300582 A EP00300582 A EP 00300582A EP 00300582 A EP00300582 A EP 00300582A EP 1033366 A2 EP1033366 A2 EP 1033366A2
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- Prior art keywords
- phenyl
- acetamide
- compound
- pyridyl
- pyridin
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- 0 **NC(C(*)I)=O Chemical compound **NC(C(*)I)=O 0.000 description 2
- LTFVELCIFWEGGA-UHFFFAOYSA-N CCN(CC)S(c(cc1)ccc1N)(=O)=O Chemical compound CCN(CC)S(c(cc1)ccc1N)(=O)=O LTFVELCIFWEGGA-UHFFFAOYSA-N 0.000 description 1
- VBVBMKJZVBPYHW-UHFFFAOYSA-N CCN(CC)S(c(cc1)ccc1NC(C(c1ccccc1)c1ccccc1)=O)(=O)=O Chemical compound CCN(CC)S(c(cc1)ccc1NC(C(c1ccccc1)c1ccccc1)=O)(=O)=O VBVBMKJZVBPYHW-UHFFFAOYSA-N 0.000 description 1
- SONXVVRXIQJXIP-UHFFFAOYSA-N CCN(CC)S(c(cc1)ccc1[N+]([O-])=O)(=O)=O Chemical compound CCN(CC)S(c(cc1)ccc1[N+]([O-])=O)(=O)=O SONXVVRXIQJXIP-UHFFFAOYSA-N 0.000 description 1
- BVYPXCFQZLNYGT-UHFFFAOYSA-N CN1CC(CN2CCCCC2)CC1 Chemical compound CN1CC(CN2CCCCC2)CC1 BVYPXCFQZLNYGT-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1S(Cl)(=O)=O)=O Chemical compound [O-][N+](c(cc1)ccc1S(Cl)(=O)=O)=O JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
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- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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Definitions
- This invention relates to the use of substituted amides which selectively bind to mammalian Neuropeptide receptors. It further relates to the use of these compounds and compositions containing these compounds in treating conditions related to an excess of neuropeptide Y such as feeding disorders and certain cardiovascular diseases.
- Neuropeptide Y a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery.
- Various animal studies have shown that activation of neuropeptide Y1 receptors is related to vasoconstriction, Wahlestedt et al. Regul. Peptides, 13 : 307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther. 261 :863-868 (1992), and Grundemar et al., Br. J. Pharmacol .
- EP0759441 and U.S. 5,576,337 report that physiological disorders related to an excess of neuropeptide Y include:
- WO 96/14307 describes substituted benzylamine derivatives which selectively bind to human neuropeptide Y1 receptors.
- This invention provides a compound of the formula I wherein:
- this invention provides a compound of formula I wherein n is zero.
- This invention also provides a compound of formula I wherein n is zero and L is 2-pyridyl or 4-pyridyl and Z is -N(C 2 H 5 ) 2 , or -SO 2 N(C 2 H 5 ) 2 .
- This invention further provides a compound of formula I wherein n is zero, Y is N and Z is or
- This invention also provides a compound of formula I wherein n is zero, Z is -SO 2 R 4 , wherein R 4 is -N(C 2 H 5 ) 2 or N(CH 3 ) 2 .
- This invention also provides a compound of formula I selected from the group consisting of:
- this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by or associated with an excess of neuropeptide Y which accompanies administering to a mammal in need of such treatment a neuropeptide Y inhibiting amount of the compound of Formula I shown above.
- This invention also comprises a method of treating a pathological condition wherein said pathological condition or physiological disorder is a feeding disorder such as obesity or bulimia.
- this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal wherein said pathological condition or physiological disorder is selected from the group consisting of:
- This invention also includes a pharmaceutical composition for inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by or associated with an excess of neuropeptide Y, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
- Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
- pharmaceutically acceptable salt(s) includes salts of acidic or basic groups that may be present in the compounds of formula I.
- pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups.
- Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of such salts is described below.
- the compounds of the present invention may have asymmetric carbon atoms.
- Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
- the compounds of formulas I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
- the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
- the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
- Those compounds of formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
- such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
- the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I.
- Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
- salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
- they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
- stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
- alkyl means a straight or branched saturated carbon chain of the specified number of carbon atoms.
- Cycloalkyl means a carbocyclic ring of the designated number of carbon atoms. Each cycloalkyl ring may be optionally substituted with one to three R groups wherein R is C 1 -C 6 alkyl.
- Halogen means F, Cl, Br or I.
- the preparation of compounds of Formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses describing the preparation of the compounds of the invention are shown in the following Schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those in the art. Purification procedures include crystallization and normal phase or reverse phase chromatography.
- an activating catalyst such as DMAP
- a base such as triethylamine
- the Z functionality in formula I can be elaborated into the requisite group after amino acid coupling.
- Z may be introduced as a carboexothy group and then the ester (provided it is the only ester in the molecule) can be saponified into the carboxylic acid such as 5 which can be further derivatized to amides such as 6 .
- the carboxylic acid can also be converted to an amine such as 7 via a Curtius Rearrangement using diphenylphosphoryl azide.
- Treatment of compounds of formula 7 with aldehydes in a suitable solvent such as HOAc or MeOH, followed by treatment with a reducing agent such as NaBH(OAc) 3 will give amines of formula 8 .
- Compounds of formula 8 can also be prepared by a palladium-catalyzed amination reaction starting from the appropriate aryl chloride, bromide or iodide such as 9 (see Wolfe, J. P.; Buchwald, S. L. Tetrahedron Letters , 1997 , 38 , 6359-6362; Wagaw, S.; Rennels, R. A.; Buchwald, S. L. JACS, 1997 , 119, 8451 -8458).
- the amines of formula 2 can be prepared by several procedures depending on the Z functionality.
- Treatment of a halo-nitro-aromatic compound 10 with an amine in the presence of a base such as sodium hydride in a polar solvent such as DMF at temperatures from 23 °C to 120 °C will provide the aromatic addition product 11 .
- Palladium-catalyzed hydrogenation of 11 in a suitable solvent such as EtOH will provide the amine 12 .
- the reduction of the nitro group can also be carried out using stannic chloride in a suitable solvent such as EtOH.
- compounds of formula 10 can be treated with NaN 3 in a suitable solvent such as DMSO, then reduced using triphenylphosphine in a suitable solvent such as THF/water, converted to the appropriately substituted nitro amines of formula 11 , and hydrogenated as described above.
- a suitable solvent such as DMSO
- triphenylphosphine in a suitable solvent such as THF/water
- carboxylic acids and nitrites serve as key intermediates in the preparation of amino-substituted heterocycles. Many of the methods are documented in A. R. Katrizky, Handbook of Heterocyclic Chemistry, Pergamon Press, 1985, New York, New York and may be used to synthesize a variety of heterocylic compounds of the present invention.
- Compounds of formula 12 can also be prepared from a halo-aromatic compound of formula 13 in which the amino group is protected.
- Treatment of 13 with an appropriate amine using a palladium catalyst such as Pd 2 (DBA) 3 as described in Buchwald references in the presence of NaO- t -Bu and a phosphine ligand such as P(o-tolyl) 3 in a solvent such as toluene at temperatures up to 100 °C will provided the amines of formula 14 . Removal of the protecting group using appropriate conditions provides amines of formula 12 .
- Amines of formula 17 can be prepared from a nitro-substituted sulfonyl chloride of formula 15 . Reaction of 15 with an amine in a suitable inert solvent such as dichloromethane at ambient temperature will provide sulfonamides of formula 16 . Reduction of the nitro group of 16 can be carried out using H 2 with Pd/C or another suitable reduction catalyst in an appropriate solvent such as ethanol, or using a reducing agent such as tin(II)chloride in an appropriate solvent such as ethanol to provide amines of formula 17 .
- Amines of formula 22 can be prepared beginning with a nitrochloropyridine of formula 18 by treatment with sodium sulfide in an appropriate solvent such as ethanol to provide a nitro disulfide of formula 19 .
- Oxidation of the disulfide under conditions such as chlorine in acetic anhydride or chlorine in an acid such as acetic, sulfuric, or nitric acid at a temperature of -20 °C will provide a nitrosulfonyl chloride of formula 20 , which can be treated with an amine (HNR 1 R 2 ) in an appropriate solvent such as dichloromethane at ambient temperature to provide a nitrosulfonamide of formula 21.
- Reduction of the nitro group can be accomplished by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a reducing agent such as tin(II)chloride to provide an aminosulfonamide of formula 22 .
- a suitable base such as sodium hydroxide
- an appropriate solvent system such as methanol-water either at ambient temperature or at reflux to provide acids of formula 26 .
- the ester may saponified using a suitable base such as sodium hydroxide in an appropriate solvent system such as methanol-water either at ambient temperature or at reflux to provide acids of formula 31 .
- Amino esters of formula 33 can be prepared from a suitable ⁇ -halo ester of formula 32 by refluxing with an appropriate amine (HNR 1 R 2 ) in a suitable solvent such as benzene (see Beuhler, C. A.; Smith, H. A.; Nayak, K. V.; Magee, T. A. J. Org.Chem. 1961 , 26 , 1573-1577; Najer, H.; Charbrier, P.; Guidicelli, R.; Sette, J. Bull. Soc. Chim. Fr . 1958, 1189-1192; Henry, R.; Dehn, W. J. Am. Chem. Soc. 1950 , 72, 2804.)
- benzene see Beuhler, C. A.; Smith, H. A.; Nayak, K. V.; Magee, T. A. J. Org.Chem. 1961 , 26 , 1573-1577; Najer, H.; Charbrier, P.; Guidicelli,
- the pharmaceutical utility of the compound of Formula I is indicated by the following assays for human NPY1 and NPY5 receptor activity.
- SK-N-MC cells were purchased from ATCC (Rockville, MD). Cells were maintained at 37°C and 5% CO 2 in Dulbecco's modified essential media (DMEM) with L-glutamine and 110 mg/L sodium pyruvate, which was supplemented with 10% fetal bovine serum and 25 mM HEPES (pH 7.3). The binding assay was performed in 24-well plates (Falcon) when the cells were confluent.
- DMEM Dulbecco's modified essential media
- HEPES 25 mM HEPES
- DPBS Dulbecco's phosphate buffered saline
- binding buffer consisting of serum-free DMEM containing 0.5% bovine serum albumin, 0.1% bacitracin and 0.1 mM phenylmethylsulfonylfluoride was added to each well.
- Nonspecific binding was defined with 1 mM NPY (porcine or human, Bachem California).
- the plates were then put on ice and the wells were aspirated.
- the cells were washed 4-6 times with 0.5 ml of ice-cold DPBS. A dilute solution of Triton X-100 (1%) was then added to each well.
- Baculovirus-infected Sf9 cells expressing recombinant human NPY 5 receptors are harvested at 48 hours. At the time of harvest, cell pellets are resuspended in lysis buffer (20 mM Tris-HCl, pH 7.4, 5 mM EDTA, 0.5 ⁇ g/ml leupeptin, 2 ⁇ g/ml Aprotonin and 200 mM PMSF) and homogenized using a Polytron (setting 3, 25-30 seconds). Homogenates are centrifuged at 4°C for 5 minutes at 200 x g ( ⁇ 1.5 rpm) to pellet the nuclei. The supernatant is collected into a fresh tube and centrifuged at 48,000 x g for 10 minutes.
- Pellets are washed once in lysis buffer and centrifuged. The final pellet is resuspended in PBS and stored in aliquots at -80°C. Purified membranes are washed using PBS and resuspended in binding buffer (50 mM Tris(HCl), pH 7.4, 5 mM KCl, 120 mM NaCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 0.1% bovine seurm albumin (BSA)).
- binding buffer 50 mM Tris(HCl), pH 7.4, 5 mM KCl, 120 mM NaCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 0.1% bovine seurm albumin (BSA)
- Membranes (20 ⁇ g/reaction tube) are added to polypropylene tubes containing 0.035 nM [ 125 I]PYY(porcine), displacers ranging from 10 -12 M to 10 -5 M, and buffer to yield a final volume of 0.5 mL.
- Nonspecific binding is determined in the presence of 1 ⁇ M NPY(human) and accounts for 10% of total binding.
- the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked GF/C Whatman filters (1.0% polyethylenemine) and rinsed 2 times with 5 mL cold binding buffer without BSA. A gamma counter is used to count filters with an efficiency of 85%.
- IC 50 values were calculated with the non-linear curve fitting program RS/1 (SigmaPlot, Jandel).
- Oocytes were prepared and maintained using standard protocols (Dascal and Lotan, in Methods in Molecular Biology; Protocols in Molecular Neurobiology, eds. Longstaff & Revest, Humana, Clifton, N.J., 13 : 1992).
- oocytes were obtained from 6 frogs. Oocytes were recorded from 2 - 7 days following coinjection of GIRKI and the H17 NPY-1 or NPY-5 subtype mRNA (25 ng of each, 50 nL total volume).
- a high K + solution containing; 1 mM NaCl, 90 mM KCl, 1 mM MgCl 2 , 1 mM CaCl 2 , 5 mM HEPES was applied to permit recording of the inwardly rectifying K + current.
- Drugs were applied diluted in the high K + media.
- NPY neuropeptide
- PP pancreatic polypeptide
- NPY neuropeptide
- PYY peptide y
- Oocytes were voltage-clamped at -80 mV with two electrodes. Oocytes were initially superfused with normal external medium (approximate flow rate 4 ml/min.). Before drugs were applied, cells were superfused with high K + solution to permit activation of the inwardly rectifying K + current. In oocytes coinjected with NPY receptor and GIRK1 mRNA, the NPY agonist induced an additional inward current over the resting K + current caused by high K + medium. Because responses desensitized at slow, but varying rates, cumulative dose applications were administered to generate concentration response curves. Two to four doses of agonist were applied to each cell. Agonist dose responses in each cell were normalized against the response to a maximal concentration of human NPY. Dose response curves were fit with a logistic equation using Kaleidagraph software (Abelbeck software, Reading, PA).
- the compound of formula I and pharmaceutically acceptable salts thereof may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier.
- the active compound may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
- compositions containing the active compound may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- an oil medium for example peanut oil liquid paraffin or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or welling agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate
- the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl or n-propyl p-hydroxybenzoate
- coloring agents for example ethyl or n-propyl p-hydroxybenzoate
- flavoring agents for example ethyl or n-propyl p-hydroxybenzoate
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example sweetening, flavoring and coloring agents, may also be present.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- Suitable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the active compound may also be administered in the form of suppositories for rectal administration of the drug.
- suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- the active compound may be administered parenterally in a sterile medium
- the drug depending on the vehicle and concentration used can either be suspended or dissolved in the vehicle.
- adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
- Dosage levels of the order of from about 0.1 mg to about 15 mg of active compound per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 7 mg to about 1 g per human patient per day).
- the amount of active compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active compound.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- the compound of the present invention possess utility for treatment of ungulate animals such as swine, cattle, sheep, and goats.
- the active compound of the invention can additionally be used for the treatment of household pets, for example companion animals such as dogs and cats.
- the administration of the active compound of formula I can be effected orally or parenterally.
- An amount of the active compound of formula I is administered such that an effective dose is received, generally a daily dose which, when administered orally to an animal is usually between 0.01 and 20 mg/kg of body weight, preferably between 0.05 and 10 mg/kg of body weight.
- the medication can be carried in drinking water so that a therapeutic dosage of the agent is ingested with the daily water supply.
- the agent can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water soluble salt).
- the active compound can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate.
- a premix or concentrate of therapeutic agent in a carrier is more commonly employed for the inclusion of the agent in the feed.
- Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds.
- a particularly effective carrier is the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the active materials in the finished feed with which the premix is blended.
- the agent may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier.
- a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like
- the proportions of active material in the concentrate are capable of wide variation since the amount of agent in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of therapeutic agent.
- High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound according to the invention.
- the mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.
- the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
- Drinking water and feed effective for treating domestic animals are generally prepared by mixing the compound of the invention with a sufficient amount of animal feed to provide from about 10 -3 to 500 ppm of the compound in the feed or water.
- the preferred medicated swine, cattle, sheep and goat feeds generally contain from 1 to 400 grams of active compound per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.
- the preferred poultry and domestic pet feeds usually contain about 1 to 400 grams and preferably 10 to 400 grams of active compound per ton of feed.
- the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought.
- parenteral administration involves injection of a sufficient amount of the compound of the present invention to provide the animal with 0.01 to 20 mg/kg/day of body weight of the active ingredient.
- the preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from 0.05 to 10 mg/kg/day of body weight of active ingredient.
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US120593 | 1998-07-22 | ||
US12059399P | 1999-02-18 | 1999-02-18 |
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EP1033366A2 true EP1033366A2 (de) | 2000-09-06 |
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EP00300582A Withdrawn EP1033366A3 (de) | 1999-02-18 | 2000-01-26 | Amid-Derivate mit Neuropeptid Y (NPY) -antagonistischer Wirkung |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1027891A2 (de) * | 1999-01-27 | 2000-08-16 | Pfizer Products Inc. | Neuropeptid Y Antagoniste |
US6407120B1 (en) | 1999-02-18 | 2002-06-18 | Pfizer Inc. | Neuropeptide Y antagonists |
WO2002083137A1 (en) * | 2001-04-12 | 2002-10-24 | Astrazeneca Ab | Use of npy y2 receptor antagonists |
WO2004013115A2 (de) * | 2002-07-26 | 2004-02-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Carbonsäureamide, deren herstellung und deren verwendung als arzneimittel |
WO2004054981A1 (en) * | 2002-12-18 | 2004-07-01 | Pfizer Products Inc. | 5-aminophenanthridine derivatives as npy-5 antagonists |
WO2005100325A1 (en) * | 2004-04-14 | 2005-10-27 | Astrazeneca Ab | Aryl glycinamide derivatives and their use as nk1 antagonists and serotonin reuptake inhibithors |
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US6610846B1 (en) | 1999-03-29 | 2003-08-26 | Hoffman-La Roche Inc. | Heteroaromatic glucokinase activators |
CA2599890C (en) * | 2005-03-03 | 2011-05-03 | H. Lundbeck A/S | Substituted pyridine derivatives |
KR102643653B1 (ko) * | 2020-11-13 | 2024-03-06 | 기초과학연구원 | 신규한 아미노방향족 화합물 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 포함하는 신경퇴행성 질환의 예방 또는 치료용 약학적 조성물 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55162757A (en) * | 1979-06-05 | 1980-12-18 | Ihara Chem Ind Co Ltd | Meta-trifluoromethylphenylacetanilide and herbicide contaning it as active constituent |
EP0184822A2 (de) * | 1984-12-11 | 1986-06-18 | Sumitomo Pharmaceuticals Company, Limited | Anilidderivate von substituierter Arylessigsäure |
WO1998003494A1 (en) * | 1996-07-23 | 1998-01-29 | Neurogen Corporation | Certain amido- and amino-substituted benzylamine derivatives; a new class of neuropeptite y1 specific ligands |
WO1998007420A1 (en) * | 1996-08-23 | 1998-02-26 | Agouron Acquisition Corp. | Neuropeptide-y ligands |
WO1998035957A1 (en) * | 1997-02-14 | 1998-08-20 | Bayer Corporation | Amide derivatives as selective neuropeptide y receptor antagonists |
-
2000
- 2000-01-26 EP EP00300582A patent/EP1033366A3/de not_active Withdrawn
- 2000-02-17 BR BR0000486-3A patent/BR0000486A/pt not_active IP Right Cessation
- 2000-02-17 JP JP2000039053A patent/JP3717737B2/ja not_active Expired - Fee Related
- 2000-02-18 CA CA002299013A patent/CA2299013C/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55162757A (en) * | 1979-06-05 | 1980-12-18 | Ihara Chem Ind Co Ltd | Meta-trifluoromethylphenylacetanilide and herbicide contaning it as active constituent |
EP0184822A2 (de) * | 1984-12-11 | 1986-06-18 | Sumitomo Pharmaceuticals Company, Limited | Anilidderivate von substituierter Arylessigsäure |
WO1998003494A1 (en) * | 1996-07-23 | 1998-01-29 | Neurogen Corporation | Certain amido- and amino-substituted benzylamine derivatives; a new class of neuropeptite y1 specific ligands |
WO1998007420A1 (en) * | 1996-08-23 | 1998-02-26 | Agouron Acquisition Corp. | Neuropeptide-y ligands |
WO1998035957A1 (en) * | 1997-02-14 | 1998-08-20 | Bayer Corporation | Amide derivatives as selective neuropeptide y receptor antagonists |
Non-Patent Citations (6)
Title |
---|
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; COVELLO, MARIO ET AL: "New iodine-containing organic compounds, N4-acylsulfanilamides" retrieved from STN Database accession no. 69:58924 XP002149212 & REND. ACCAD. SCI. FIS. MAT. (SOC. NAZ. SCI., LETT. ARTI NAPOLI) (1966), 33(DEC.), 304-8 , * |
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; IONESCU, MARIA ET AL: "Action of p-nitrosodimethylaniline on pyruvic acid and its derivatives. IV" retrieved from STN Database accession no. 70:19762 XP002149211 & STUD. UNIV. BABES-BOLYAI, SER. CHEM. (1968), 13(1), 95-8 , * |
DATABASE REGISTRY [Online] CHEMICAL ABSTRACT SERVICE, COLUMBUS, OHIO, US; XP002149210 * |
HASSNER, ALFRED ET AL: "Synthetic methods. Part 23. Rearrangement of some hydroxamic acids into amides. A self-condensation leading to disproportionation" J. CHEM. SOC., PERKIN TRANS. 1 (1988), (4), 733-7 , XP002149208 * |
JOHN G. TOPLISS: "A Novel Elimination Reation of o-Acylaminobenzenesulfonamides" JOURNAL OF ORGANIC CHEMISTRY, vol. 28, 1963, pages 2595-2598, XP002149209 * |
PATENT ABSTRACTS OF JAPAN vol. 005, no. 041 (C-047), 18 March 1981 (1981-03-18) & JP 55 162757 A (IHARA CHEM IND CO LTD), 18 December 1980 (1980-12-18) -& JP 55 162757 A 18 December 1980 (1980-12-18) * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1027891A2 (de) * | 1999-01-27 | 2000-08-16 | Pfizer Products Inc. | Neuropeptid Y Antagoniste |
EP1027891A3 (de) * | 1999-01-27 | 2002-07-17 | Pfizer Products Inc. | Neuropeptid Y Antagoniste |
US6407120B1 (en) | 1999-02-18 | 2002-06-18 | Pfizer Inc. | Neuropeptide Y antagonists |
WO2002083137A1 (en) * | 2001-04-12 | 2002-10-24 | Astrazeneca Ab | Use of npy y2 receptor antagonists |
WO2004013115A2 (de) * | 2002-07-26 | 2004-02-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Carbonsäureamide, deren herstellung und deren verwendung als arzneimittel |
WO2004013115A3 (de) * | 2002-07-26 | 2004-04-08 | Boehringer Ingelheim Pharma | Carbonsäureamide, deren herstellung und deren verwendung als arzneimittel |
WO2004054981A1 (en) * | 2002-12-18 | 2004-07-01 | Pfizer Products Inc. | 5-aminophenanthridine derivatives as npy-5 antagonists |
US6958347B2 (en) | 2002-12-18 | 2005-10-25 | Pfizer Inc. | Aminophenanthridinone and aminophenanthridine as NPY-5 antagonists |
WO2005100325A1 (en) * | 2004-04-14 | 2005-10-27 | Astrazeneca Ab | Aryl glycinamide derivatives and their use as nk1 antagonists and serotonin reuptake inhibithors |
Also Published As
Publication number | Publication date |
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CA2299013A1 (en) | 2000-08-18 |
JP3717737B2 (ja) | 2005-11-16 |
EP1033366A3 (de) | 2000-12-27 |
CA2299013C (en) | 2004-09-28 |
JP2000239243A (ja) | 2000-09-05 |
BR0000486A (pt) | 2001-08-21 |
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